Crohn's Disease and Colitis Are Linked to Mutant Gene

By NICHOLAS BAKALAR

Published: November 7, 2006

A team of American and Canadian researchers have identified a major gene associated with Crohn's disease and ulcerative colitis, two closely related diseases collectively known as inflammatory bowel disease, or I.B.D. The discovery may help in finding more effective treatments.

The Centers for Disease Control and Prevention estimates that I.B.D., which is more common among Ashkenazi Jews than other groups, affects more than a million Americans.

Crohn's disease causes breaks in the lining of the small and large intestines and can affect the entire digestive system. Ulcerative colitis is usually restricted to the large intestine and involves inflammation of more superficial layers of the bowel lining, while Crohn's also affects deeper layers. In some cases, the intestinal wall can be punctured, causing abscesses, infection and fever.

In addition to intestinal problems -- cramps, diarrhea and rectal bleeding -- Crohn's can also cause painful skin ulcers, eye conditions that can interfere with vision, inflammation of the liver and arthritis, among other complications. Symptoms usually begin in adolescence or young adulthood and then intermittently flare up.

There are treatments for Crohn's, but no cure. Anti-inflammatory drugs, immune system suppressants, antibiotics and surgery are all used, with varying degrees of success. Most treatments have side effects that can range from trivial to debilitating.

Various causes for Crohn's have been proposed, including diet, infections with specific bacteria, possible environmental factors and immune system disorders. But most scientists believe that an immune response to normally beneficial intestinal bacteria in genetically susceptible people is the cause. Understanding this susceptibility may allow the development of treatments that will specifically target the key immune response pathways.

In this study, researchers compared the genomes of Crohn's patients of European descent, both Jewish and non-Jewish, to those of healthy controls of the same ancestries. More than 1,900 subjects were involved in the analysis. The report appears online in the Oct. 26 issue of Science Express.

The researchers examined more than 300,000 single nucleotide polymorphisms, or SNPs (pronounced ''snips''), the variations that occur when a nucleotide, a molecular subunit of DNA, is altered. They found that the frequency of variations in the gene for a receptor of a protein called interleukin-23, or IL-23, was significantly different in people with Crohn's disease compared with healthy people. After finding the difference in Crohn's patients, they found it in ulcerative colitis sufferers as well. This genetic variation leads to a susceptibility to the inflammation that characterizes I.B.D.

The IL-23 receptor gene is not the only one thought to be associated with I.B.D., but it seems an especially good candidate. ''The IL-23 immune pathway was already implicated in I.B.D., psoriasis, rheumatoid arthritis and multiple sclerosis,'' said Dr. Richard H. Duerr, the study's lead author and an associate professor of medicine at the University of Pittsburgh.

Animal models offer further evidence. Mice genetically engineered to express a subunit of IL-23 suffer severe systemic inflammation, including in the small and large intestines.

''This immune pathway has been very intensively studied over the past year or so, and is probably involved in multiple organ inflammations,'' said Dr. Judy H. Cho, the senior author of the paper and an associate professor of medicine at Yale. ''So the genetic findings in the IL-23 receptor made sense in the context of what was already known about the importance of the IL-23 pathway.''

She added, ''It's a nice confluence of animal studies and human genetics, with potential therapeutic implications.''

The researchers discovered a coding variant that apparently protects against I.B.D., because it is found less frequently in patients than in healthy controls. This ''is one of the most exciting aspects of the work,'' Dr. Duerr said, adding, ''If we can mimic the effects of this protective variant, we may be able to more effectively manage patients with I.B.D.''